Pulse generator for irreversible electroporation

ABSTRACT

A medical apparatus includes a probe configured for insertion into a body of a patient. The probe includes a plurality of electrodes configured to contact tissue within the body. The medical apparatus further includes an electrical signal generator configured to apply between one or more pairs of the electrodes signals of first and second types in alternation. The signals of the first type include a sequence of bipolar pulses having an amplitude sufficient to cause irreversible electrophoresis (IRE) in the tissue contacted by the electrodes. The signals of the second type include a radio-frequency (RF) signal having a power sufficient to thermally ablate the tissue contacted by the electrodes.

FIELD OF THE INVENTION

The present invention relates generally to medical equipment, andparticularly to apparatus and methods for irreversible electroporation(IRE).

BACKGROUND

Irreversible electroporation (IRE) is a soft tissue ablation techniquethat applies short pulses of strong electrical fields to createpermanent and hence lethal nanopores in the cell membrane, thusdisrupting the cellular homeostasis (internal physical and chemicalconditions). Cell death following IRE results from apoptosis (programmedcell death) and not necrosis (cell injury, which results in thedestruction of a cell through the action of its own enzymes) as in allother thermal or radiation based ablation techniques. IRE is commonlyused in tumor ablation in regions where precision and conservation ofthe extracellular matrix, blood flow and nerves are of importance.

SUMMARY

Exemplary embodiments of the present invention that are describedhereinbelow provide improved systems and methods for irreversibleelectroporation.

There is therefore provided, in accordance with an exemplary embodimentof the present invention, a medical apparatus, which includes a probeconfigured for insertion into a body of a patient and which includes aplurality of electrodes configured to contact tissue within the body,and an electrical signal generator configured to apply between one ormore pairs of the electrodes signals of first and second types inalternation. The signals of the first type include a sequence of bipolarpulses having an amplitude sufficient to cause irreversibleelectroporation (IRE) in the tissue contacted by the electrodes, and thesignals of the second type include a radio-frequency (RF) signal havinga power sufficient to thermally ablate the tissue contacted by theelectrodes.

In a disclosed exemplary embodiment, the electrical signal generator isfurther configured to apply the signals of the first type without thealternation with the signals of the second type. Additionally oralternatively, the electrical signal generator is configured to applythe signals of the second type without the alternation with the signalsof the first type.

In some exemplary embodiments, the sequence of bipolar pulses includespulses having an amplitude of at least 200 V, and a duration of each ofthe bipolar pulses is less than 20 μs. Additionally or alternatively,the RF signal has a frequency between 350 and 500 kHz and an amplitudebetween 10 and 200 V.

In some exemplary embodiments, the medical apparatus includes acontroller configured to transmit control signals to the electricalsignal generator. The electrical signal generator includes a pulsegeneration assembly, configured to receive the control signals from thecontroller and to transmit sequences of bipolar pulses with an amplitudeand duration responsive to the control signals. The electrical signalgenerator further includes a pulse routing and metrology assembly, whichincludes a configurable network of multiple, mutually connected fastswitches and slow relays, which are configured to receive the controlsignals from the controller, to receive the sequences of bipolar pulsesfrom the pulse generation assembly, and to transmit the sequences ofbipolar pulses to the plurality of electrodes responsively to thereceived control signals. In a disclosed exemplary embodiment, theelectrical signal generator includes a low-pass filter, which isconfigured to receive and filter a pulse train from the pulse generationassembly so as to convert the pulse train to the RF signal, therebygenerating the signals of the second type.

In a disclosed exemplary embodiment, the signals of the first typeinclude pairs of pulses, where each pair includes a positive pulse and anegative pulse, and where the signals of the second type are interleavedbetween the positive and negative pulses of the pairs. Alternatively,the signals of the second type are interleaved between successive pairsof the pulses.

In some exemplary embodiments, the electrical signal generator isconfigured to generate a plurality of pulse trains, wherein each pulsetrain includes the signals of the first and second types, and whereinthe pulse trains are separated by intervals in which the signals are notapplied.

In a further exemplary embodiment, the probe includes a plurality oftemperature sensors adjacent to the electrodes, and the electricalsignal generator is configured to apply the signals responsively to atemperature measured by the temperature sensors.

In a disclosed exemplary embodiment, the probe is configured to contactthe tissue in a heart of the patient and to apply the signals so as toablate the tissue in the heart. In one exemplary embodiment, theelectrical signal generator is configured to apply the signalsasynchronously with respect to a beating of the heart. Alternatively,the electrical signal generator is configured to apply the signalssynchronously with respect to a beating of the heart.

In another exemplary embodiment, the electrical signal generator isconfigured to apply, during a first period of time while the probecontacts a locus in the tissue, between each electrode and a firstneighboring electrode on a first side of the electrode in the array, afirst sequence of the bipolar pulses having an amplitude sufficient tocause irreversible electroporation (IRE) in the tissue between eachelectrode and the first neighboring electrode. The electrical signalgenerator is further configured to apply during a second period of timewhile the probe remains in contact with the locus in the tissue, betweeneach electrode and a second neighboring electrode on a second side ofthe electrode, opposite the first side, in the array, a second sequenceof the bipolar pulses capable of causing IRE in the tissue between theelectrode and the second neighboring electrode.

There is also provided, in accordance with an exemplary embodiment ofthe present invention, a medical apparatus, including a probe configuredfor insertion into a body of a patient, wherein the probe includes anarray of electrodes disposed along the probe and configured to contacttissue within the body. An electrical signal generator is configured toapply during a first period of time while the probe contacts a locus inthe tissue, between each electrode and a first neighboring electrode ona first side of the electrode in the array, a first sequence of bipolarpulses having an amplitude sufficient to cause irreversibleelectroporation (IRE) in the tissue between each electrode and the firstneighboring electrode. The electrical signal generator is furtherconfigured to apply during a second period of time while the proberemains in contact with the locus in the tissue, between each electrodeand a second neighboring electrode on a second side of the electrode,opposite the first side, in the array, a second sequence of bipolarpulses capable of causing IRE in the tissue between the electrode andthe second neighboring electrode.

In a disclosed exemplary embodiment, the electrical signal generator isfurther configured to apply sequences of the bipolar pulses betweenpairs of electrodes that are separated by at least one other electrodein the array, with an amplitude sufficient to cause irreversibleelectroporation (IRE) in the tissue between the electrodes in the pairs.

There is additionally provided, in accordance with an exemplaryembodiment of the present invention, a method for ablating tissue withina body of a patient. The method includes inserting a probe into thebody, wherein the probe includes a plurality of electrodes configured tocontact the tissue. The method further includes applying between one ormore pairs of the plurality of electrodes signals of first and secondtypes in alternation. The signals of the first type include a sequenceof bipolar pulses having an amplitude sufficient to cause irreversibleelectroporation (IRE) in the tissue contacted by the electrodes, and thesignals of the second type include a radio-frequency (RF) signal havinga power sufficient to thermally ablate the tissue contacted by theelectrodes.

There is further provided, in accordance with an exemplary embodiment ofthe present invention, a method for ablating tissue within a body of apatient. The method includes inserting a probe into the body, whereinthe probe includes a plurality of electrodes disposed along the probeand configured to contact the tissue. The method further includesapplying during a first period of time while the probe contacts a locusin the tissue, between each electrode and a first neighboring electrodeon a first side of the electrode in the array, a first sequence ofbipolar pulses having an amplitude sufficient to cause irreversibleelectroporation (IRE) in the tissue between each electrode and the firstneighboring electrode. During a second period of time while the proberemains in contact with the locus in the tissue, a second sequence ofbipolar pulses capable of causing IRE in the tissue is applied betweeneach electrode and a second neighboring electrode on a second side ofthe electrode, opposite the first side, in the array.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be more fully understood from the followingdetailed description of the embodiments thereof, taken together with thedrawings in which:

FIG. 1 is a schematic pictorial illustration of a multi-channel IREsystem used in an IRE ablation procedure, in accordance with exemplaryembodiments of the present invention;

FIG. 2 is a schematic illustration of a bipolar IRE pulse, in accordancewith an exemplary embodiment of the present invention;

FIG. 3 is a schematic illustration of a burst of bipolar pulses, inaccordance with an exemplary embodiment of the present invention;

FIGS. 4A-B are schematic illustrations of IRE signals with anincorporated RF signal, in accordance with an exemplary embodiment ofthe present invention;

FIG. 5 is a block diagram that schematically illustrates an IRE moduleand its connections to other modules, in accordance with an exemplaryembodiment of the present invention;

FIG. 6 is an electrical schematic diagram of a pulse routing andmetrology assembly in the IRE module of FIG. 5 ;

FIG. 7 is an electrical schematic diagram of two adjacent modules in thepulse routing and metrology assembly of FIG. 6 ;

FIG. 8 is an electrical schematic diagram of a pulse generating circuit,a transformer, and a high-voltage supply, in accordance with anexemplary embodiment of the present invention; and

FIG. 9 is an electrical schematic diagram of a switch, in accordancewith an exemplary embodiment of the present invention.

DETAILED DESCRIPTION OF EMBODIMENTS Overview

IRE is a predominantly non-thermal process, which causes an increase ofthe tissue temperature by, at most, a few degrees for a fewmilliseconds. It thus differs from RF (radio frequency) ablation, whichraises the tissue temperature by between 20 and 70° C. and destroyscells through heating. IRE utilizes bipolar pulses, i.e., combinationsof positive and negative pulses, in order to avoid muscle contractionfrom a DC voltage. The pulses are applied, for example, between twobipolar electrodes of a catheter.

In order for the IRE-pulses to generate the required nanopores intissue, the field strength E of the pulses must exceed atissue-dependent threshold Eth. Thus, for example, for heart cells thethreshold is approximately 500 V/cm, whereas for bone it is 3000 V/cm.These differences in threshold field strengths enable IRE to be appliedselectively to different tissues. In order to achieve the required fieldstrength, the voltage to be applied to a pair of electrodes depends bothon the targeted tissue and on the separation between the electrodes. Theapplied voltages may reach up to 2000 V, which is much higher than thetypical voltage of 10-200 V in thermal RF ablation.

A bipolar IRE-pulse comprises a positive and a negative pulse appliedbetween two electrodes with pulse widths of 0.5-5 μs and a separationbetween the positive and negative pulses of 0.1-5 μs. Herein the terms“positive” and “negative” refer to an arbitrarily chosen polaritybetween the two electrodes. The bipolar pulses are assembled into pulsetrains, each train comprising between one and a hundred bipolar pulses,with a pulse-to-pulse period of 1-20 μs. To perform IRE ablation at agiven location, between one and a hundred pulse trains are appliedbetween a pair of electrodes at the location, with a spacing betweenconsecutive pulse trains of 0.3-1000 ms. The total energy per channel(electrode-pair) delivered in one IRE ablation is typically less than 60J, and an ablation may last up to 10 s.

When a multi-electrode catheter is used in an IRE procedure, successivepairs of electrodes may be cycled through during the procedure. Takingas an example a 10-electrode catheter, the electrode pairs may beenergized in an adjacent fashion (1-2, 2-3, . . . 9-10) or in aninterleaved fashion (1-3, 2-4, . . . 8-10). However, energizing, forexample, adjacent pairs must be done in two stages, first energizing theodd-even electrodes 1-2, 3-4, 5-6, 7-8 and 9-10, and then the even-oddelectrodes 2-3, 4-5, 6-7, and 8-9. Using commonly available sources,such as signal generators or defibrillators, to drive the electrodes,the required switching from one set of electrodes (odd-even) to anotherset of electrodes (even-odd) is done either manually or using slowswitches.

The exemplary embodiments of the present invention that are describedherein address the requirements for switching between sets of electrodesby providing a medical apparatus comprising a versatile electricalsignal generator for IRE, with capabilities of fast switching andgeneration of a variety of therapeutic signals. The signal generatoroperates in conjunction with a probe, comprising a catheter withmultiple electrodes arrayed along the catheter, which is inserted intothe body of the patient so that the electrodes contact tissue within thebody.

Each electrode along the catheter (except the first and last electrodesin the array) has neighboring electrodes on both sides. In someexemplary embodiments, during a first period of time, the signalgenerator applies IRE pulses between each electrode and a first of itstwo neighbors, for example between pairs 1-2, 3-4, . . . 9-10. Then,during a second period of time it applies the IRE pulses between eachelectrode and its second neighbor, for example, pairs 2-3, 4-5, . . .8-9. In other words, by defining the labels “first neighbor” and “secondneighbor” appropriately, the above application of IRE pulses energizesthe odd-even electrodes during the first period of time and the even-oddelectrodes during the second period of time.

In the disclosed exemplary embodiments, the signal generator, configuredas an IRE generator, comprises a network of fast switches, enablingswitching between the odd-even and even-odd electrodes in a matter ofmilliseconds or less. By incorporating additional relays in the network,it may be configured for applying the IRE pulses to other configurationsof electrodes, such as, for example, interleaved electrodes, with aconcomitant fast switching between sets of interleaved electrodes.

As noted earlier, the two commonly used methods of ablation, IREablation and RF ablation, implement different modalities: IRE ablationdestroys cells by punching holes in the cell membranes, whereas RFablation destroys the cells by heating. It can be advantageous tocombine these two methods in treating the same tissue.

Thus, in some exemplary embodiments of the present invention that aredescribed herein, the electrical signal generator is capable ofswitching rapidly between the two modalities of IRE ablation and RFablation. The electrical signal generator thus applies an alternatingsequence of IRE pulses and a RF signal between one or more pairs of theelectrodes.

In the disclosed exemplary embodiments, the signal generator, configuredas an IRE generator, functions in two rapidly switchable modalities: Inan IRE modality, it generates IRE pulses for IRE ablation; in an RFmodality, the signal generator generates a pulse train at a frequencysuitable for RF ablation and with a lower amplitude than IRE pulses.This pulse train is converted to a sinusoidal RF ablation signal byfiltering it through a low-pass filter. Rapid switching between thesetwo modalities, while coupling both the IRE and the RF ablation signalsto the same electrodes, is accomplished by alternatingly closing andopening a bypass switch in parallel with the low-pass filter. The RFablation signal may be inserted either between two consecutive bipolarIRE pulses or between the positive and negative pulses of a singlebipolar IRE pulse. In the latter case, the spacing between the positiveand negative pulse is stretched to 1-10 ms.

The IRE generator is controlled by an IRE controller implementing anablation protocol. The protocol defines the values for all of theparameters of the IRE ablation, including an additionally incorporatedRF ablation in some cases, to suit the targeted tissue and the electrodeconfiguration of the catheter. These parameter values are set at thestart of the IRE procedure by a medical professional, such as aphysician, controlling the procedure. The physician sets the parametersbased on the required tissue volume, field strength, catheterconfiguration, and the energy per pulse or pulse train, as well as theenergy to be delivered over the entire procedure.

Ire Ablation System and Ire Pulses

FIG. 1 is a schematic pictorial illustration of a multi-channel IREsystem 20 used in an IRE ablation procedure, in accordance withexemplary embodiments of the present invention. In the followingdescription, the IRE ablation procedure will also be referred to as “IREablation” or “IRE procedure.” In the illustrated exemplary embodiment, aphysician 22 is performing a multi-channel IRE ablation procedure usingIRE system 20. Physician 22 is performing the procedure on a subject 24,using an ablation catheter 26 whose distal end 28 comprises multipleablation electrodes 30 arrayed along the length of the catheter.

IRE system 20 comprises a processor 32 and an IRE module 34, wherein theIRE module comprises an IRE generator 36 and an IRE controller 38. Aswill be further detailed below, IRE generator 36 generates trains ofelectrical pulses, which are directed to selected electrodes 30 forperforming an IRE procedure. The waveforms (timing and amplitude) of thetrains of electrical pulses are controlled by IRE controller 38.Processor 32, as will also be detailed below, handles the input andoutput interface between IRE system 20 and physician 22.

Processor 32 and IRE controller 38 each typically comprises aprogrammable processor, which is programmed in software and/or firmwareto carry out the functions that are described herein. Alternatively oradditionally, each of them may comprise hard-wired and/or programmablehardware logic circuits, which carry out at least some of thesefunctions. Although processor 32 and IRE controller 38 are shown in thefigures, for the sake of simplicity, as separate, monolithic functionalblocks, in practice some of these functions may be combined in a singleprocessing and control unit, with suitable interfaces for receiving andoutputting the signals that are illustrated in the figures and aredescribed in the text. In some exemplary embodiments, IRE controller 38resides within IRE module 34, as high-speed control signals aretransmitted from the IRE controller to IRE generator 36. However,provided that signals at sufficiently high speeds may be transmittedfrom processor 32 to IRE generator 36, IRE controller 38 may residewithin the processor.

Processor 32 and IRE module 34 typically reside within a console 40.Console 40 comprises input devices 42, such as a keyboard and a mouse. Adisplay screen 44 is located in proximity to (or integral to) console40. Display screen 44 may optionally comprise a touch screen, thusproviding another input device.

IRE system 20 may additionally comprise one or more of the followingmodules (typically residing within console 40), connected to suitableinterfaces and devices in system 20:

-   -   An electrocardiogram (ECG) module 46 is coupled through a cable        48 to ECG electrodes 50, which are attached to subject 24. ECG        module 46 is configured to measure the electrical activity of a        heart 52 of subject 24.    -   A temperature module 54 is coupled to optional temperature        sensors, such as thermocouples 56 located adjacent to each        electrode 30 on distal end 28 of catheter 26, and is configured        to measure the temperature of adjacent tissue 58.    -   A tracking module 60 is coupled to one or more electromagnetic        position sensors (not shown) in distal end 28. In the presence        of an external magnetic field generated by one or more        magnetic-field generators 62, the electromagnetic position        sensors output signals that vary with the positions of the        sensors. Based on these signals, tracking module 60 may        ascertain the positions of electrodes 30 in heart 52.

The above modules 46, 54, and 60 typically comprise both analog anddigital components, and are configured to receive analog signals andtransmit digital signals. Each module may additionally comprisehard-wired and/or programmable hardware logic circuits, which carry outat least some of the functions of the module.

Catheter 26 is coupled to console 40 via an electrical interface 64,such as a port or socket. IRE signals are thus carried to distal end 28via interface 64. Similarly, signals for tracking the position of distalend 28, and/or signals for tracking the temperature of tissue 58, may bereceived by processor 32 via interface 64 and applied by IRE controller38 in controlling the pulses generated by IRE generator 36.

An external electrode 65, or “return patch”, may be additionally coupledexternally between subject 24, typically on the skin of the subject'storso, and IRE generator 36.

Processor 32 receives from physician 22 (or from other user), prior toand/or during the IRE procedure, setup parameters 66 for the procedure.Using one or more suitable input devices 42, physician 22 sets theparameters of the IRE pulse train, as explained below with reference toFIGS. 2-4 and Table 1. Physician 22 further selects pairs of ablationelectrodes 30 for activation (for receiving the IRE pulse trains) andthe order in which they are activated.

In setting up the IRE ablation, physician 22 may also choose the mode ofsynchronization of the burst of IRE pulses with respect to the cycle ofheart 52. A first option, which is called a “synchronous mode,” is tosynchronize the IRE pulse burst to take place during the refractorystate of heart 52, when the heart is recharging and will not respond toexternal electrical pulses. The burst is timed to take place after theQRS-complex of heart 52, wherein the delay is approximately 50% of thecycle time of the heart, so that the burst takes place during the T-waveof heart 52, before the P-wave. In order to implement synchronous mode,IRE controller 38 times the burst or bursts of IRE pulses based on ECGsignals 414 from ECG module 46, shown in FIG. 5 , below.

A second synchronization option is an asynchronous mode, wherein theburst of IRE pulses is launched independently of the timing of heart 52.This option is possible, since the IRE burst, typically of a length of200 ms, with a maximal length of 500 ms, is felt by the heart as oneshort pulse, to which the heart does not react. Asynchronous operationof this sort can be useful in simplifying and streamlining the IREprocedure.

In response to receiving setup parameters 66, processor 32 communicatesthese parameters to IRE controller 38, which commands IRE generator 36to generate IRE signals in accordance with the setup requested byphysician 22. Additionally, processor 32 may display setup parameters 66on display screen 44.

In some exemplary embodiments, processor 32 displays on display 44,based on signals received from tracking module 60, a relevant image 68of the subject's anatomy, annotated, for example, to show the currentposition and orientation of distal end 28. Alternatively oradditionally, based on signals received from temperature module 54 andECG module 46, processor 32 may display on display screen 44 thetemperatures of tissue 58 at each electrode 30 and the electricalactivity of heart 52.

To begin the procedure, physician 22 inserts catheter 26 into subject24, and then navigates the catheter, using a control handle 70, to anappropriate site within, or external to, heart 52. Subsequently,physician 22 brings distal end 28 into contact with tissue 58, such asmyocardial or epicardial tissue, of heart 52. Next, IRE generator 36generates multiple IRE signals, as explained below with reference toFIG. 3 . The IRE signals are carried through catheter 26, over differentrespective channels, to pairs of ablation electrodes 30, such thatcurrents 72 generated by the IRE pulses flow between the electrodes ofeach pair (bipolar ablation), and perform the requested irreversibleelectroporation on tissue 58.

FIG. 2 is a schematic illustration of a bipolar IRE pulse 100, inaccordance with an exemplary embodiment of the present invention.

A curve 102 depicts the voltage V of bipolar IRE pulse 100 as a functionof time t in an IRE ablation procedure. The bipolar IRE pulse comprisesa positive pulse 104 and a negative pulse 106, wherein the terms“positive” and “negative” refer to an arbitrarily chosen polarity of thetwo electrodes 30 between which the bipolar pulse is applied. Theamplitude of positive pulse 104 is labeled as V+, and the temporal widthof the pulse is labeled as t+. Similarly, the amplitude of negativepulse 106 is labeled as V−, and the temporal width of the pulse islabeled as t−. The temporal width between positive pulse 104 andnegative pulse 106 is labeled as t_(SPACE). Typical values for theparameters of bipolar pulse 100 are given in Table 1, below.

FIG. 3 is a schematic illustration of a burst 200 of bipolar pulses, inaccordance with an exemplary embodiment of the present invention.

In an IRE procedure, the IRE signals are delivered to electrodes 30 asone or more bursts 200, depicted by a curve 202. Burst 200 comprisesN_(T) pulse trains 204, wherein each train comprises N_(P) bipolarpulses 100. The length of pulse train 204 is labeled as t_(T). Theperiod of bipolar pulses 100 within a pulse train 204 is labeled ast_(PP), and the interval between consecutive trains is labeled as Δ_(T),during which the signals are not applied. Typical values for theparameters of burst 200 are given in Table 1, below.

FIGS. 4A-B are schematic illustrations of IRE signals 302 and 304 withan incorporated RF signal, in accordance with exemplary embodiments ofthe present invention. In the exemplary embodiments shown in FIGS. 4A-B,RF ablation is combined with IRE ablation in order to benefit from bothof these ablation modalities.

In FIG. 4A, a curve 306 depicts the voltage V as a function of time t ofan RF signal 308 between two bipolar pulses 310 and 312, similar tobipolar pulse 100 of FIG. 2 . The amplitude of RF signal 308 is labeledas V_(RF) and its frequency is labeled as f_(RF), and the separationbetween bipolar pulses 310 and 312 is labeled as Δ_(RF). Typically thefrequency f_(RF) is between 350 and 500 kHz, and the amplitude V_(RF) isbetween 10 and 200 V, but higher or lower frequencies and amplitudes mayalternatively be used.

In FIG. 4B, a curve 314 depicts the voltage V as a function of time t ofan RF signal 316 between a positive IRE pulse 318 and a negative IREpulse 320. IRE pulses 318 and 320 are similar to pulses 104 and 106 ofFIG. 2 . In this exemplary embodiment, the spacing t_(SPACE) betweenpositive and negative pulses 318 and 320 has been stretched, asindicated in Table 1.

Typical values of the amplitude and frequency of RF signals 308 and 316are given in Table 1. When an RF signal is inserted into the IRE signal,as depicted either in FIG. 4A or FIG. 4B, the combination of the twosignals is repeated to the end of the ablation procedure.

TABLE 1 Typical values for the parameters of IRE signals ParameterSymbol Typical values Pulse amplitudes V+, V− 500-2000 V Pulse widthst+, t− 0.5-5 μs Spacing between t_(SPACE) 0.1-5 μs positive and  (1-10ms when an optional RF negative pulse  signal is inserted between the positive and negative pulses) Period of bipolar t_(PP) 1-20 μs pulsesin a pulse train Length of pulse t_(T) 100 μs train Number of bipolarN_(P) 1-100 pulses in a pulse train Spacing between Δ_(T) 0.3-1000 msconsecutive pulse trains Number of pulse N_(T) 1-100 trains in a burstLength of a burst 0-500 ms Energy per channel ≤60 J Total time for IRE≤10 s signal delivery Amplitude of V_(RF) 10-200 V optional RF signalFrequency of f_(RF) 500 kHz optional RF signal

Ire Module

FIG. 5 is a block diagram that schematically shows details of IRE module34 and its connections to other modules in system 20, in accordance withan exemplary embodiment of the present invention.

With reference to FIG. 1 , IRE module 34 comprises IRE generator 36 andIRE controller 38. IRE module 34 is delineated in FIG. 5 by an outerdotted-line frame 402. Within frame 402, IRE generator 36 is delineatedby an inner dotted-line frame 404. IRE generator 36 comprises a pulsegeneration assembly 406 and a pulse routing and metrology assembly 408,which will both be further detailed in FIGS. 6-9 , below.

IRE controller 38 communicates with processor 32 through bi-directionalsignals 410, wherein the processor communicates to the IRE controllercommands reflecting setup parameters 66. IRE controller 38 furtherreceives digital voltage and current signals 412 from pulse routing andmetrology assembly 408, digital ECG signals 414 from ECG module 46, anddigital temperature signals 416 from temperature module 54, andcommunicates these signals through bi-directional signals 410 toprocessor 32.

IRE controller 38 communicates to pulse generation assembly 406 digitalcommand signals 418, derived from setup parameters 66, commanding IREgenerator 36 to generate IRE pulses, such as those shown in FIGS. 3-5 ,above. These IRE pulses are sent to pulse routing and metrology assembly408 as analog pulse signals 420. Pulse routing and metrology assembly408 is coupled to electrodes 30 through output channels 422, as well asto return patch 65 through connection 424. FIG. 5 shows ten outputchannels 422, labelled CH1-CH10. In the following description, aspecific electrode is called by the name of the specific channel coupledto it; for example, electrode CH5 relates to the electrode that iscoupled to CH5 of channels 422. Although FIG. 5 refers to ten channels422, IRE generator may alternatively comprise a different number ofchannels, for example 8, 16, or 20 channels, or any other suitablenumber of channels.

FIG. 6 is an electrical schematic diagram of pulse routing and metrologyassembly 408 of FIG. 5 , in accordance with an exemplary embodiment ofthe present invention. For the sake of clarity, the circuits involved inmeasuring currents and voltages, have been omitted. These circuits willbe detailed in FIG. 7 , below. Output channels 422 and connection 424are shown in FIG. 6 using the same labels as in FIG. 5 .

Pulse routing and metrology assembly 408 comprises modules 502, with onemodule for each output channel 422. A pair 504 of adjacent modules 502is shown in detail in FIG. 7 , below.

Each module 502 comprises switches, labelled as FO_(i), SO_(i), N_(i),and BP_(i) for the i^(th) module. Switches FO_(i) are all fast switchesfor switching the IRE ablation from channel to channel, whereas switchesSO_(i), N_(i), and BP_(i) are slower relays, used to set up pulserouting and metrology assembly 408 for a given mode of IRE ablation. Atypical switching time for fast switches FO_(i) is shorter than 0.3 μs,whereas slow relays SO_(i), N_(i), and BP_(i) require a switching timeof only 3 ms. The examples that are given below demonstrate uses of theswitches and relays.

Example 1 demonstrates the use of the switches and relays for IREablation between pairs of electrodes according to an odd-even schemeCH1-CH2, CH3-CH4, CH5-CH6, CH7-CH8, and CH9-CH10. (Here the bipolarpulses are applied between each electrode and a first neighbor.) Thesettings of the switches and relays are shown in Table 2, below.

TABLE 2 Switch and relay settings for Example 1 Channel Fast switch Slowrelay Slow relay Slow relay CH_(i) FO_(i) SO_(i) N_(i) BPi CH1 ON ON ONOFF CH2 OFF ON ON OFF CH3 ON ON ON OFF CH4 OFF ON ON OFF CH5 ON ON ONOFF CH6 OFF ON ON OFF CH7 ON ON ON OFF CH8 OFF ON ON OFF CH9 ON ON ONOFF CH10 OFF ON ON OFF

Example 2 demonstrates the use of the switches and relays for IREablation between pairs of electrodes according to an even-odd schemeCH2-CH3, CH4-CH5, CH6-CH7, and CH8-CH9 (in which the bipolar pulses areapplied between each electrode and its second neighbor). For a circularcatheter 26, wherein the first and last of electrodes lie side-by-side,the pair CH10-CH1 may be added to the even-odd pairs. The settings ofthe switches and relays are shown in Table 3, below.

TABLE 3 Switch and relay settings for Example 2 Channel Fast switch Slowrelay Slow relay Slow relay CH_(i) FO_(i) SO_(i) N_(i) BPi CH1 OFF ON ONOFF CH2 ON ON ON OFF CH3 OFF ON ON OFF CH4 ON ON ON OFF CH5 OFF ON ONOFF CH6 ON ON ON OFF CH7 OFF ON ON OFF CH8 ON ON ON OFF CH9 OFF ON ONOFF CH10 ON ON ON OFF

Combining Examples 1 and 2, a fast IRE ablation between all pairs ofelectrodes 30 may be accomplished by first ablating with the even-oddscheme of Example 1, then switching each fast switch FO_(i) to anopposite state (from ON to OFF and from OFF to ON), and then ablatingwith the odd-even scheme of Example 2. As slow relays SO_(i), N_(i), andBP_(i) are not required to switch their states, the switching takesplace at the speed of the FO_(i) switches.

Example 3 demonstrates IRE ablation between non-adjacent electrodes 30,in this example CH1-CH3, CH4-CH6, and CH7-CH9. Such a configuration maybe utilized to cause deeper lesions in tissue 58. The settings of theswitches and relays are shown in Table 4, below.

TABLE 4 Switch and relay settings for Example 3 Channel Fast switch Slowrelay Slow relay Slow relay CH_(i) FO_(i) SO_(i) N_(i) BPi CH1 ON ON ONOFF CH2 ON ON ON OFF CH3 OFF ON ON OFF CH4 ON ON ON OFF CH5 ON ON ON OFFCH6 OFF ON ON OFF CH7 ON ON ON OFF CH8 ON ON ON OFF CH9 OFF ON ON OFFCH10 OFF ON ON OFF

Again, other pairs of electrodes may be rapidly chosen by reconfiguringswitches FO_(i).

Example 4 demonstrates an alternative way to perform an ablation betweenchannels CH1 and CH3. In this example, a BP line 506 is utilized toclose the ablation circuit. The settings of the switches and relays areshown in Table 5, below.

TABLE 5 Switch and relay settings for Example 4 Channel Fast switch Slowrelay Slow relay Slow relay CH_(i) FO_(i) SO_(i) N_(i) BPi CH1 ON ON OFFON CH2 OFF ON OFF OFF CH3 ON ON OFF ON CH4 OFF ON OFF OFF CH5 ON ON OFFOFF CH6 OFF ON OFF OFF CH7 ON ON OFF OFF CH8 OFF ON OFF OFF CH9 ON ONOFF OFF CH10 OFF ON OFF OFF

In Example 4, the electrical path in pulse routing and metrologyassembly 408 couples transformer secondaries 508 and 510 in series. Asthe distance between electrodes CH1 and CH3 is double to that betweenadjacent electrodes (for example CH1 and CH2), the voltage between CH1and CH3 has to be double the voltage between adjacent electrodes so asto have the same electrical field strength between the respectiveelectrodes. This is accomplished by driving the primaries for these twosecondaries in opposite phases. Slow switches SO_(i) are all left in theON-state in preparation for the next ablation between another pair ofelectrodes, for example between CH2 and CH4.

As shown in the above examples, the implementation of pulse routing andmetrology assembly 408 using relays and fast switches enables a flexibleand fast distribution of IRE pulses to electrodes 30, as well as aflexible re-configuration of the applied IRE pulse amplitudes.

FIG. 7 is an electrical schematic diagram of two adjacent modules 601and 602 of pulse routing and metrology assembly 408, in accordance withan exemplary embodiment of the present invention.

Modules 601 and 602 make up pair 504 of FIG. 6 , as is shown by dash-dotframe with the same label (504). Modules 601 and 602 are fed by pulsegenerating circuits 603 and 604, respectively, which comprise, withreference to FIG. 5 , parts of pulse generation assembly 406. Modules601 and 602, in turn, feed channels CH1 and CH2, respectively, similarlyto modules 502 of pair 504 in FIG. 6 . Two modules 601 and 602 are shownin FIG. 7 in order to show a connection 605 between the modules. As thetwo modules are identical (and identical to the additional modules inpulse routing and metrology assembly 408), only module 601 is describedin detail below.

Further details of pulse generating circuits 603 and 604 are shown inFIGS. 8-9 , below. Pulse generation assembly 406 comprises one pulsegenerating circuit similar to circuits 603 and 604 for each channel ofIRE generator 36. Pulse generation assembly 406 further comprises ahigh-voltage supply 607, detailed in FIG. 8 .

Pulse generating circuit 603 is coupled to module 601 by a transformer606. Fast switch FO₁ and slow relays SO₁, N₁, and BP₁ are labelledsimilarly to FIG. 6 . A low-pass filter 608 converts a pulse traintransmitted by pulse generating circuit 603 via transformer 606 andswitch FO₁ to a sinusoidal signal, allowing CH1 to be used for RFablation. (Similarly, each channel of IRE generator 36 may beindependently used for RF ablation.) The engagement of filter 608 iscontrolled by a relay 610. An RF signal having a given frequency f_(RF)and amplitude V_(RF) is produced by pulse generating circuit 603emitting a train of bipolar pulses at the frequency f_(RF) throughlow-pass filter 608, which converts this pulse train to a sinusoidalsignal with the frequency f_(RF). The amplitude of the train of bipolarpulses is adjusted so that the amplitude of the sinusoidal signal isV_(RF).

A voltage V₁ and current I₁ coupled to CH1 are shown in FIG. 7 as avoltage between channels CH1 and CH2, and a current flowing to CH1 andreturning from CH2.

V₁ and I₁ are measured by a metrology module 612, comprising anoperational amplifier 614 for measuring the voltage and a differentialamplifier 616 measuring the current across a current sense resistor 618.Voltage V₁ is measured from a voltage divider 620, comprising resistorsR₁, R₂, and R₃, and an analog multiplexer 622. Analog multiplexer 622couples in either resistor R₁ or R₂, so that the voltage dividing ratioof voltage divider 620 is either R₁/R₃ or R₂/R₃. Metrology module 612further comprises an analog-to-digital converter (ADC) 624 forconverting the measured analog voltage V₁ and current I₁ to digitalsignals DV₁ and DI₁. These digital signals are sent through a digitalisolator 626 to IRE controller 38 as signals 412 (FIG. 5 ). Digitalisolator 626 protects subject 24 (FIG. 1 ) from unwanted electricalvoltages and currents.

Switch FO₁, relays SO₁, BP₁, N₁ and 610, and analog multiplexer 622 aredriven by IRE controller 38. For the sake of simplicity, the respectivecontrol lines are not shown in FIG. 7 .

FIG. 8 is an electrical schematic diagram of pulse generating circuit603, transformer 606, and high-voltage supply 607, in accordance with anexemplary embodiment of the present invention.

Pulse generating circuit 603 (FIG. 7 ) comprises two switches 702 and704, whose internal details are further shown in FIG. 9 , below. Switch702 comprises a command input 706, a source 708, and a drain 710. Switch704 comprises a command input 712, a source 714, and a drain 716.Together switches 702 and 704 form a half of an H-bridge (as is known inthe art), also called a “half bridge.”

High-voltage supply 607 supplies to respective outputs 720 and 722 apositive voltage V+ and a negative voltage V−, adjustable withinrespective positive and negative ranges of ±(10-2000) V responsively toa signal received by a high-voltage command input 724 from IREcontroller 38. High-voltage supply 607 also provides a ground connection723. A single high-voltage supply 607 is coupled to all pulse generatingcircuits of pulse generation assembly 406. Alternatively, each pulsegenerating circuit may be coupled to a separate high-voltage supply.

Drain 710 of switch 702 is coupled to positive voltage output 720, andsource 708 of the switch is coupled to an input 726 of transformer 606.When command input 706 receives a command signal CMD+, positive voltageV+ is coupled from positive voltage output 720 to transformer input 726via switch 702. Source 714 of switch 704 is coupled to negative voltageoutput 722, and drain 716 of the switch is coupled to transformer input726. When command input 712 receives a command signal CMD−, negativevoltage V− is coupled from negative voltage output 722 to transformerinput 726 via switch 704. Thus, by alternately activating the twocommand signals CMD+ and CMD−, positive and negative pulses,respectively, are coupled to transformer input 726, and then transmittedby transformer 606 to its output 728. The timing of the pulses (theirwidths and separation) are controlled by command signals CMD+ and CMD−,and the amplitudes of the pulses are controlled by a high-voltagecommand signal CMD_(HV) to high-voltage command input 724. All threecommand signals CMD+, CMD−, and CMD_(HV) are received from IREcontroller 38, which thus controls the pulses fed into the respectivechannel of pulse routing and metrology assembly 408.

In an alternative exemplary embodiment (not shown in the figures), afull H-bridge is utilized, with a single-polarity high-voltage supply.This configuration may also be used to produce both positive andnegative pulses from the single-polarity source, in response to signalscontrolling the full H-bridge. An advantage of this embodiment is thatit can use a simpler high-voltage supply, whereas the advantage of ahalf bridge and a dual high-voltage power supply is that it provides afixed ground potential, as well as independently adjustable positive andnegative voltages.

FIG. 9 is an electrical schematic diagram of switch 702, in accordancewith an exemplary embodiment of the present invention. Switch 704 isimplemented in a similar fashion to switch 702.

The switching function of switch 702 is implemented by a field-effecttransistor (FET) 802, comprising a gate 804, source 708, and drain 710.Command input 706 is coupled to gate 804, with source 708 and drain 710coupled as shown in FIG. 8 . Additional components 806, comprising Zenerdiodes, a diode, a resistor, and a capacitor, function as circuitprotectors.

It will be appreciated that the embodiments described above are cited byway of example, and that the present invention is not limited to whathas been particularly shown and described hereinabove. Rather, the scopeof the present invention includes both combinations and subcombinationsof the various features described hereinabove, as well as variations andmodifications thereof which would occur to persons skilled in the artupon reading the foregoing description and which are not disclosed inthe prior art.

The invention claimed is:
 1. A medical apparatus for tissue ablation,comprising: a probe having a distal end, a proximal end and a lengthconfigured for insertion into a body of a patient and comprising anarray of electrodes disposed successively along the length of the probeconfigured to contact tissue within the body, the array of electrodeshaving a proximal electrode at the proximal end of the probe and adistal electrode at distal end of the probe and a plurality ofintermediary electrodes between the proximal and distal electrodes; andan electrical signal generator configured to apply between one or morepairs of the array of electrodes, signals of first and second types inalternation, the signals of the first type comprising a plurality ofsequences of bipolar pulses, each sequence of the bipolar pulses havinga duration and an amplitude sufficient to cause irreversibleelectroporation (IRE) in the tissue contacted by the array ofelectrodes, a first sequence of bipolar pulses of the plurality ofsequences of bipolar pulses being applied to odd-even pairs ofelectrodes for all of the array of electrodes during a first period oftime, the odd-even pairs of electrodes beginning with a pair comprisingthe proximal electrode and an electrode of the plurality of intermediaryelectrodes immediately adjacent the proximal electrode and continuingsuccessively for each remaining pair of the electrodes in the array, anda second sequence of bipolar pulses of the plurality of sequences ofbipolar pulses being applied to even-odd pairs of electrodes of thearray of electrodes during a second period of time, the even-odd pairsof electrodes beginning with a pair comprising the electrode immediatelyadjacent the proximal electrode and a successive immediately adjacentelectrode of the plurality of intermediary electrodes and continuingsuccessively for each remaining pair of the of electrodes in the array,and the signals of the second type comprising a radio-frequency (RF)signal having a power sufficient to thermally ablate the tissuecontacted by the electrodes.
 2. The medical apparatus according to claim1, wherein the electrical signal generator is further configured toapply the signals of the first type without the alternation with thesignals of the second type.
 3. The medical apparatus according to claim1, wherein the electrical signal generator is further configured toapply the signals of the second type without the alternation with thesignals of the first type.
 4. The medical apparatus according to claim1, wherein each of the plurality of sequences of bipolar pulsescomprises pulses, the amplitude being at least 200 V, and the durationof each of the bipolar pulses being less than 20 μs.
 5. The medicalapparatus according to claim 1, wherein the RF signal has a frequencybetween 350 and 500 kHz and an amplitude between 10 and 200 V.
 6. Themedical apparatus according to claim 1, and comprising a controllerconfigured to transmit control signals to the electrical signalgenerator, and wherein the electrical signal generator comprises: apulse generation assembly, configured to receive the control signalsfrom the controller and to transmit the plurality of sequences ofbipolar pulses responsive to the control signals; and a pulse routingand metrology assembly, comprising a configurable network of multiple,mutually connected fast switches and slow relays, which are configuredto receive the control signals from the controller, to receive theplurality of sequences of bipolar pulses from the pulse generationassembly, and to transmit the plurality of sequences of bipolar pulsesto the plurality of electrodes responsively to the received controlsignals.
 7. The medical apparatus according to claim 6, wherein theelectrical signal generator comprises a low-pass filter, which isconfigured to receive and filter a pulse train from the pulse generationassembly so as to convert the pulse train to the RF signal, therebygenerating the signals of the second type.
 8. The medical apparatusaccording to claim 1, wherein each of the plurality of sequences ofbipolar pulses of the signals of the first type comprises a positivepulse and a negative pulse, and wherein the signals of the second typeare interleaved between the positive and negative pulses of each of theplurality of sequences of bipolar pulses of the signals of the firsttype.
 9. The medical apparatus according to claim 1, wherein each of theplurality of sequences of bipolar pulses of the signals of the firsttype comprises a positive pulse and a negative pulse, and wherein thesignals of the second type are interleaved between successive sequencesof the plurality of sequences of bipolar pulses.
 10. The medicalapparatus according to claim 1, wherein the electrical signal generatoris configured to generate a plurality of pulse trains, each pulse traincomprising the signals of the first and second types, wherein the pulsetrains are separated by intervals in which the signals are not applied.11. The medical apparatus according to claim 1, wherein the probecomprises a plurality of temperature sensors adjacent to the pluralityof electrodes, and wherein the electrical signal generator is configuredto apply the signals responsively to a temperature measured by thetemperature sensors.
 12. The medical apparatus according to claim 1,wherein the probe is configured to contact the tissue in a heart of thepatient and to apply the signals so as to ablate the tissue in theheart.
 13. The medical apparatus according to claim 10, wherein theelectrical signal generator is configured to apply the signalsasynchronously with respect to a beating of the heart.
 14. The medicalapparatus according to claim 13, wherein the electrical signal generatoris configured to apply the signals synchronously with respect to abeating of the heart.
 15. A medical apparatus for tissue ablation,comprising: a probe having a distal end, a proximal end and a lengthconfigured for insertion into a body of a patient and comprising anarray of electrodes disposed successively along the length of the probeand configured to contact tissue within the body, the array having aproximal electrode at the proximal end of the probe and a distalelectrode at distal end of the probe and a plurality of intermediaryelectrodes between the proximal and distal electrodes; and an electricalsignal generator configured to apply during a first period of time whilethe probe contacts a locus in the tissue, between one or more pairs ofelectrodes in the array, signals comprising a first sequence of bipolarpulses having a duration and an amplitude sufficient to causeirreversible electroporation (IRE) in the tissue between each pair ofodd-even electrodes, the first sequence being applied beginning with apair of electrodes comprising the proximal electrode and an electrode inthe plurality of intermediary electrodes immediately adjacent theproximal electrode and continuing successively for each remaining pairof the electrodes in the array, and to apply during a second period oftime while the probe remains in contact with the locus in the tissue,between even-odd electrodes in the array, signals comprising a secondsequence of bipolar pulses having an amplitude sufficient to cause IREin the tissue between each even-odd electrodes, the second sequencebeing applied beginning with a pair of electrodes comprising theelectrode immediately adjacent proximal electrode and a successiveimmediately adjacent electrode of the plurality of intermediaryelectrodes and continuing successively for each remaining pair of theelectrodes in the array.
 16. The medical apparatus according to claim15, wherein each of the plurality of sequences of bipolar pulsescomprises pulses, the amplitude being at least 200 V, and the durationof each of the bipolar pulses being less than 20 μs.
 17. The medicalapparatus according to claim 15, wherein the electrical signal generatoris configured to generate a plurality of pulse trains comprising thefirst and second sequences of bipolar pulses, wherein the pulse trainsare separated by intervals in which the first and second sequences ofbipolar pulses are not applied.
 18. The medical apparatus according toclaim 15, wherein the probe is configured to contact the tissue in aheart of the patient and to apply the first and second sequences of thebipolar pulses so as to ablate the tissue in the heart.
 19. The medicalapparatus according to claim 18, wherein the electrical signal generatoris configured to apply the signals asynchronously with respect to abeating of the heart.
 20. The medical apparatus according to claim 18,wherein the electrical signal generator is configured to apply thesignals synchronously with respect to a beating of the heart.
 21. Themedical apparatus according to claim 15, wherein the probe comprises aplurality of temperature sensors adjacent to the array of electrodes,and wherein the electrical signal generator is configured to apply thefirst and second sequences of bipolar pulses responsively to atemperature measured by the temperature sensors.
 22. The medicalapparatus according to claim 15, wherein the electrical signal generatoris further configured to apply the first and second sequences of thebipolar pulses between pairs of electrodes that are separated by atleast one other electrode in the array, the amplitude of the bipolarpulses being sufficient to cause irreversible electroporation (IRE) inthe tissue between the electrodes in the pairs.
 23. A method forablating tissue within a body of a patient, the method comprising:inserting a probe having a distal end, a proximal end and a length intothe body, wherein the probe comprises an array of electrodes disposedsuccessively along the length of the probe and configured to contact thetissue, the array having a proximal electrode at the proximal end of theprobe and a distal electrode at distal end of the probe and a pluralityof intermediary electrodes between the proximal and distal electrodes;and applying between one or more pairs of the array of electrodes of thearray, signals of first and second types in alternation, the signals ofthe first type comprising a first sequence of bipolar pulses having aduration and an amplitude sufficient to cause irreversibleelectroporation (IRE) in the tissue, the first sequence of bipolarpulses being applied to odd-even pairs of electrodes in the array duringa first period of time while the probe contacts a locus in the tissue,the first sequence being applied beginning with a pair of electrodescomprising the proximal electrode and an electrode of the plurality ofintermediary electrodes immediately adjacent the proximal electrode andcontinuing successively for each remaining pair of electrodes in thearray, and a second sequence of bipolar pulses having a duration and anamplitude sufficient to cause IRE in the tissue between each even-oddpairs of electrodes in the array during a second period of time whilethe probe remains in contact with the locus, the second sequence beingapplied beginning with a pair of electrodes comprising the electrodeimmediately adjacent the proximal electrode and a successive immediatelyadjacent electrode of the plurality of intermediary electrodes andcontinuing successively for each remaining pair of electrodes in thearray, and the signals of the second type comprising a radio-frequency(RF) signal having a power sufficient to thermally ablate the tissuecontacted by the electrodes.
 24. The method according to claim 23,wherein each of the plurality of sequences of bipolar pulses comprisespulses the amplitude is at least 200 V, and the duration of each of thebipolar pulses is less than 20 μs.
 25. The method according to claim 23,wherein the RF signal has a frequency of between 350 and 500 kHz and anamplitude of between 10 and 200 V.
 26. The method according to claim 23,wherein applying the signals of the first and second types comprisesgenerating a each of the first and second sequences of bipolar pulseswherein the amplitude and the duration are selected, and configuring anetwork of multiple, mutually connected fast switches and slow relays totransmit the sequences of bipolar pulses to the plurality of electrodes.27. The method according to claim 26, wherein applying the signals ofthe second type comprises applying a low-pass filter to convert thesecond sequences of pulses into the RF signal, thereby generating thesignals of the second type.
 28. The method according to claim 23,wherein applying the signals of the first type comprises applyingsequences of bipolar pulses, wherein each sequence comprises a positivepulse and a negative pulse, and wherein applying signals of the secondtype comprises interleaving the signals of the second type between thepositive and negative pulses of the sequences.
 29. The method accordingto claim 23, wherein applying the signals of the first type comprisesapplying sequences of bipolar pulses, wherein each sequence comprises apositive pulse and a negative pulse, and wherein applying signals of thesecond type comprises interleaving the signals of the second typebetween successive sequences of the pulses.
 30. The method according toclaim 23, wherein applying the signals of the first and second typescomprises applying a plurality of pulse trains, each pulse traincomprising the signals of the first and second types, and separating thepulse trains by intervals in which the signals of the first and secondtypes are not applied.
 31. The method according to claim 23, andcomprising measuring a temperature of the tissue using a plurality oftemperature sensors adjacent to the plurality of electrodes, whereinapplying the signals of the first and second types comprises controllingthe signals of the first and second types responsively to thetemperature measured by the temperature sensors.
 32. The methodaccording to claim 23, wherein inserting the probe comprises bringingthe plurality of electrodes into contact with the tissue in a heart ofthe patient, and wherein applying the signals of the first and secondtypes comprises ablating the tissue in the heart.
 33. The methodaccording to claim 32, wherein applying the signals of the first andsecond types comprises applying the signals of the first and secondtypes asynchronously with respect to a beating of the heart.
 34. Themethod according to claim 32, wherein applying the signals of the firstand second types comprises applying the signals of the first and secondtypes synchronously with respect to a beating of the heart.
 35. A methodfor ablating tissue within a body of a patient, the method comprising:inserting a probe having a length into the body, wherein the probecomprises an array of a plurality of electrodes disposed successivelyalong the length of the probe and configured to contact the tissue, thearray having a proximal electrode at a proximal end of the probe and adistal electrode at a distal end of the probe and a plurality ofintermediary electrodes between the proximal and distal electrodes; andapplying during a first period of time while the probe contacts a locusin the tissue, between odd-even pairs of electrodes in the array,signals comprising a first sequence of bipolar pulses having a durationand an amplitude sufficient to cause irreversible electroporation (IRE)in the tissue between each odd-even electrodes, the first sequence beingapplied beginning with a pair of electrodes comprising the proximalelectrode and an electrode of the plurality of intermediary electrodesimmediately adjacent the proximal electrode and continuing successivelyfor each remaining pair of the electrodes in the array, and applyingduring a second period of time while the probe remains in contact withthe locus in the tissue, between each even-odd electrodes in the array,signals comprising a second sequence of bipolar pulses having anamplitude sufficient to cause IRE in the tissue between each even-oddelectrodes, the second sequence being applied beginning with a pair ofelectrodes comprising the electrode immediately adjacent the proximalelectrode and a successive immediately adjacent electrode of theplurality of intermediary electrodes and continuing successively foreach remaining pair of electrodes in the array.
 36. The method accordingto claim 35, wherein each of the plurality of sequences of bipolarpulses comprises pulses, the amplitude being at least 200 V, and theduration of each of the bipolar pulses being less than 20 μs.
 37. Themethod according to claim 35, wherein applying the signals of first andsecond types comprises applying a plurality of pulse trains comprisingthe first and second sequences of bipolar pulses, wherein the pulsetrains are separated by intervals in which the bipolar pulses are notapplied.
 38. The method according to claim 35, wherein inserting theprobe comprises bringing the electrodes into contact with the tissue ina heart of the patient, and wherein applying the signals of the firstand second types comprises ablating the tissue in the heart.
 39. Themethod according to claim 38, wherein applying the signals of the firstand second types comprises applying the signals of the first and secondtypes asynchronously with respect to a beating of the heart.
 40. Themethod according to claim 38, wherein applying the signals comprisesapplying the signals of the first and second types synchronously withrespect to a beating of the heart.
 41. The method according to claim 35,and comprising measuring a temperature of the tissue using a pluralityof temperature sensors adjacent to the plurality of electrodes, whereinapplying the signals of the first and second types comprises controllingthe signals of the first and second types responsively to thetemperature measured by the temperature sensors.
 42. The methodaccording to claim 35, and further comprising applying the first andsecond sequences of the bipolar pulses between pairs of electrodes thatare separated by at least one other electrode in the array, theamplitude of the bipolar pulses being sufficient to cause irreversibleelectroporation (IRE) in the tissue between the electrodes in the pairs.